A fundamental understanding of the molecular mechanism governing osteoblast differentiation is essential for developing novel bone anabolic therapeutics. Physiological Notch signaling has emerged as a critical suppressive mechanism for osteoblast differentiation to ensure a proper pool of mesenchymal progenitors necessary for long-term bone homeostasis. Hyperactivation of NOTCH2 has recently been discover to cause Hajdu-Cheney syndrome (HCS) characterized by childhood osteoporosis, acroosteolysis and wormian bones. Where or not osteoblast or osteoclast defects are the primary cause for the disease has not been established. Moreover, an effective treatment for the disease is currently lacking. Elucidating the cellular basis for the disease and the relationship between NOTCH and other regulators of bone physiology will provide the basis for a rational design of therapeutics. I the current proposal, we test the hypothesis that suppression of osteoblast differentiation by hyperactive NOTCH2 is primarily responsible for HCS, and that stimulation of the bone anabolic WNT pathway may alleviate the bone defects associated with the disease. We further investigate the biochemical basis for the functional antagonism between NOTCH and WNT signaling. Overall, successful completion of this project is expected to provide novel mechanistic insights about the pathogenesis of HCS, and may open new avenues for effective treatments of the disease.